Polymorphic forms of the sodium salt of 4-tert- butyl -n-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzene sulfonamide

ABSTRACT

Disclosed are novel polymorphic solvated and desolvated forms of the sodium salt of 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide and pharmaceutical compositions containing the same. Also disclosed are processes for the preparation thereof and methods for use thereof.

REFERENCE TO EARLIER FILED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/289,629, which is a divisional of U.S. application Ser. No.14/832,755, filed Aug. 21, 2015, which is a divisional of U.S.application Ser. No. 14/234,279, filed Jan. 22, 2014, which is a 371national phase of PCT/US2012/047513, filed Jul. 20, 2012, and claims thebenefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No.61/510,559, filed Jul. 22, 2011, the disclosures of which areincorporated, in their entirety, by this reference.

BACKGROUND OF THE INVENTION

In the pursuit of a developable form of a solid, orally-administeredpharmaceutical compound, a number of specific features are sought.Although an amorphous form of a pharmaceutical compound may bedeveloped, compounds having high crystallinity are generally preferred.Often such highly crystalline compounds are salts.

International Publication Number WO 2004/046092 describes a series ofcompounds which are indicated as antagonists of the CCR9 receptor, andwhich are indicated as being useful in the treatment of CCR9-mediateddisorders. Specifically disclosed in that application is the compound4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide.Identification of a stable, crystalline form of such compound withsuitable properties for oral administration would be highly desirablefor the treatment of CCR9-mediated diseases.

SUMMARY OF THE INVENTION

The present invention relates to novel polymorphic solvated ordesolvated forms of the sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(hereinafter “Compound A”). The compounds of the invention arerepresented by Structure (I):

and, specifically, compounds where X is a solvent or solvent mixturesuch as 1,4-dioxane/water, formamide, dimethylsulfoxide, or water, orwhere X is absent. The compounds of this invention are useful forantagonizing the CCR9 receptor, and for treating diseases such asinflammatory bowel disease, including Crohn's disease and ulcerativecolitis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction pattern of CompoundA—1,4-dioxane/water solvate.

FIG. 2 shows an X-ray powder diffraction pattern of Compound A—formamidesolvate.

FIG. 3 shows an X-ray powder diffraction pattern of CompoundA—dimethylsulfoxide solvate.

FIG. 4 shows an X-ray powder diffraction pattern of CompoundA—desolvated crystalline form.

FIG. 5 shows an X-ray powder diffraction pattern of Compound A—hydrate.

FIG. 6 shows a Raman spectrum of Compound A—1,4-dioxane/water solvate.

FIG. 7 shows a Raman spectrum of Compound A—formamide solvate.

FIG. 8 shows a Raman spectrum of Compound A—dimethylsulfoxide solvate.

FIG. 9 shows a Raman spectrum of Compound A—desolvated crystalline form.

FIG. 10 shows a differential scanning calorimetry trace of CompoundA—1,4-dioxane/water solvate.

FIG. 11 shows a differential scanning calorimetry trace of CompoundA—formamide solvate.

FIG. 12 shows a differential scanning calorimetry trace of CompoundA—dimethylsulfoxide solvate.

FIG. 13 shows a differential scanning calorimetry trace of CompoundA—desolvated crystalline form.

FIG. 14 shows a thermogravimetric analysis trace of CompoundA—1,4-dioxane/water solvate.

FIG. 15 shows a thermogravimetric analysis trace of Compound A—formamidesolvate.

FIG. 16 shows a thermogravimetric analysis trace of CompoundA—dimethylsulfoxide solvate.

FIG. 17 shows a thermogravimetric analysis trace of CompoundA—desolvated crystalline form.

FIG. 18 shows a thermogravimetric analysis trace of Compound A—hydrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel polymorphic solvated anddesolvated forms of the sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide.One embodiment of the present invention is directed to a crystallinesodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(hereinafter “Compound A—1,4-dioxane/water solvate”), wherein thecrystalline form is characterized by an X-ray powder diffraction patterncomprising diffraction angles (°2θ), when measured using Cu K_(α)radiation, at about 4.0, 8.1, 10.1, 14.2, 16.2, 18.6, 20.3, 24.7, 25.0,and 26.5.

Another embodiment of the present invention is directed to CompoundA—1,4-dioxane/water solvate, wherein the crystalline form ischaracterized by an X-ray powder diffraction pattern substantially inaccordance with FIG. 1.

Another embodiment of the present invention is directed to CompoundA—1,4-dioxane/water solvate, wherein the crystalline form provides aRaman spectrum containing peaks at about 668, 743, 804, 1125, 1154,1162, 1286, 1544, 1587, 1597, 1611, 1657, and 1672 cm⁻¹.

Another embodiment of the present invention is directed to CompoundA—1,4-dioxane/water solvate, wherein the crystalline form provides aRaman spectrum substantially in accordance with FIG. 6.

Another embodiment of the present invention is directed to CompoundA—1,4-dioxane/water solvate, wherein the crystalline form provides adifferential scanning calorimetry trace substantially in accordance withFIG. 10 and/or a thermogravimetric analysis trace substantially inaccordance with FIG. 14.

Another embodiment of the present invention is directed to a crystallinesodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(hereinafter “Compound A—formamide solvate”), wherein the crystallineform is characterized by an X-ray powder diffraction pattern comprisingdiffraction angles (°2θ), when measured using Cu K_(α) radiation, atabout 5.9, 8.6, 12.1, 12.7, 16.1, 16.9, 17.4, 17.8, 18.0, 20.4, 20.6,21.7, 22.6, 23.7, 23.9, 24.3, 25.9, 26.3, 26.5, 26.9, 27.9, 30.9, and38.6.

Another embodiment of the present invention is directed to CompoundA—formamide solvate, wherein the crystalline form is characterized by anX-ray powder diffraction pattern substantially in accordance with FIG.2.

Another embodiment of the present invention is directed to CompoundA—formamide solvate, wherein the crystalline form provides a Ramanspectrum containing peaks at about 655, 668, 737, 804, 1079, 1099, 1123,1161, 1229, 1303, 1465, 1537, 1595, 1611, and 1654 cm⁻¹.

Another embodiment of the present invention is directed to CompoundA—formamide solvate, wherein the crystalline form provides a Ramanspectrum substantially in accordance with FIG. 7.

Another embodiment of the present invention is directed to CompoundA—formamide solvate, wherein the crystalline form provides adifferential scanning calorimetry trace substantially in accordance withFIG. 11 and/or a thermogravimetric analysis trace substantially inaccordance with FIG. 15.

Another embodiment of the present invention is directed to a crystallinesodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(hereinafter “Compound A—dimethylsulfoxide solvate”), wherein thecrystalline form is characterized by an X-ray powder diffraction patterncomprising diffraction angles (°2θ), when measured using Cu K_(α)radiation, at about 5.6, 8.0, 10.8, 15.7, 17.0, 17.7, 18.0, 18.1, 18.4,21.2, 21.8, 22.5, 22.8, 24.3, 28.6, 29.7, and 34.5.

Another embodiment of the present invention is directed to CompoundA—dimethylsulfoxide solvate, wherein the crystalline form ischaracterized by an X-ray powder diffraction pattern substantially inaccordance with FIG. 3.

Another embodiment of the present invention is directed to CompoundA—dimethylsulfoxide solvate, wherein the crystalline form provides aRaman spectrum containing peaks at about 662, 672, 718, 729, 750, 799,1078, 1109, 1158, 1236, 1302, 1536, 1588, 1596, and 1636 cm⁻¹.

Another embodiment of the present invention is directed to CompoundA—dimethylsulfoxide solvate, wherein the crystalline form provides aRaman spectrum substantially in accordance with FIG. 8.

Another embodiment of the present invention is directed to CompoundA—dimethylsulfoxide solvate, wherein the crystalline form provides adifferential scanning calorimetry trace substantially in accordance withFIG. 12 and/or a thermogravimetric analysis trace substantially inaccordance with FIG. 16.

Another embodiment of the present invention is directed to a crystallinesodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(hereinafter “Compound A—desolvated crystalline form”), wherein thecrystalline form is characterized by an X-ray powder diffraction patterncomprising diffraction angles (°2θ), when measured using Cu K_(α)radiation, at about 6.5, 9.6, 10.6, 11.9, 14.4, 16.1, 17.7, 17.9, 19.3,21.1, 22.0, 22.2, 23.4, 23.6, 24.4, 26.3, 27.7, 28.5, and 29.5.

Another embodiment of the present invention is directed to CompoundA—desolvated crystalline form, wherein the crystalline form ischaracterized by an X-ray powder diffraction pattern substantially inaccordance with FIG. 4.

Another embodiment of the present invention is directed to CompoundA—desolvated crystalline form, wherein the crystalline form provides aRaman spectrum containing peaks at about 654, 667, 737, 803, 855, 1077,1122, 1160, 1311, 1461, 1536, 1592, 1609, and 1648 cm⁻¹.

Another embodiment of the present invention is directed to CompoundA—desolvated crystalline form, wherein the crystalline form provides aRaman spectrum substantially in accordance with FIG. 9.

Another embodiment of the present invention is directed to CompoundA—desolvated crystalline form, wherein the crystalline form provides adifferential scanning calorimetry trace substantially in accordance withFIG. 13 and/or a thermogravimetric analysis trace substantially inaccordance with FIG. 17.

Another embodiment of the present invention is directed to a crystallinesodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(hereinafter “Compound A—hydrate”), wherein the crystalline form ischaracterized by an X-ray powder diffraction pattern comprisingdiffraction angles (°2θ), when measured using Cu K_(α) radiation, atabout 6.1, 12.4, 15.9, 16.4, 16.9, 17.8, 18.0, 19.1, 23.4, and 25.0.

Another embodiment of the present invention is directed to CompoundA—hydrate, wherein the crystalline form is characterized by an X-raypowder diffraction pattern substantially in accordance with FIG. 5.

Another embodiment of the present invention is directed to CompoundA—hydrate, wherein the crystalline form provides a thermogravimetricanalysis trace substantially in accordance with FIG. 18.

It is well known and understood to those skilled in the art that theapparatus employed, humidity, temperature, orientation of the powdercrystals, and other parameters involved in obtaining an X-ray powderdiffraction (XRPD) pattern may cause some variability in the appearance,intensities, and positions of the lines in the diffraction pattern. AnX-ray powder diffraction pattern that is “substantially in accordance”with that of FIG. 1, 2, 3, 4, or 5 provided herein is an XRPD patternthat would be considered by one skilled in the art to represent acompound possessing the same crystal form as the compound that providedthe XRPD pattern of FIG. 1, 2, 3, 4, or 5. That is, the XRPD pattern maybe identical to that of FIG. 1, 2, 3, 4, or 5, or more likely it may besomewhat different. Such an XRPD pattern may not necessarily show eachof the lines of the diffraction patterns presented herein, and/or mayshow a slight change in appearance, intensity, or a shift in position ofsaid lines resulting from differences in the conditions involved inobtaining the data. A person skilled in the art is capable ofdetermining if a sample of a crystalline compound has the same form as,or a different form from, a form disclosed herein by comparison of theirXRPD patterns. For example, one skilled in the art can overlay an XRPDpattern of a sample of a sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide,with FIG. 1 and, using expertise and knowledge in the art, readilydetermine whether the XRPD pattern of the sample is substantially inaccordance with the XRPD pattern of Compound A—1,4-dioxane/watersolvate. If the XRPD pattern is substantially in accordance with FIG. 1,the sample form can be readily and accurately identified as having thesame form as Compound A—1,4-dioxane/water solvate. Similarly, a personskilled in the art is capable of determining if a given diffractionangle (expressed in °2θ) obtained from an XRPD pattern is at about thesame position as a value presented herein.

“A compound of the invention” means a sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide,specifically the crystalline forms defined herein as CompoundA—1,4-dioxane/water solvate, Compound A—formamide solvate, CompoundA—dimethylsulfoxide solvate, Compound A—desolvated crystalline form, andCompound A—hydrate.

The invention includes a therapeutic method for treating or amelioratinga CCR9-mediated disorder in a subject in need thereof comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition comprising an effectiveamount of a compound of the invention and an optional pharmaceuticallyacceptable carrier.

As used herein, the phrase “CCR9-mediated disorder” and related phrasesand terms refer to a condition or disease characterized byinappropriate, i.e., less than or greater than normal, CCR9 functionalactivity. Inappropriate CCR9 functional activity might arise as theresult of CCR9 expression in cells which normally do not express CCR9,increased CCR9 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CCR9 expression.Inappropriate CCR9 functional activity might also arise as the result ofTECK secretion by cells which normally do not secrete TECK, increasedTECK expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases) or decreased TECK expression. A CCR9-mediateddisorder may be completely or partially mediated by inappropriate CCR9functional activity. However, a CCR9-mediated disorder is one in whichmodulation of CCR9 results in some effect on the underlying condition ordisease (e.g., a CCR9 antagonist results in some improvement in patientwell being in at least some patients).

“Effective amount” means that amount of drug substance (i.e. a compoundof the present invention) that elicits the desired biological responsein a subject. Such response includes alleviation of the symptoms of thedisease or disorder being treated. The effective amount of a compound ofthe invention in such a therapeutic method is about 0.001 to 100 mg perkg patient body weight per day which can be administered in single ormultiple doses. Preferably, the dosage level will be about 0.01 to about25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.A suitable dosage level may be about 0.01 to 25 mg/kg per day, about0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within thisrange the dosage may be 0.005 to 0.05, 0.05 to 0.5, 0.5 to 5.0, or 5.0to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0,20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

It is to be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including age, body weight, hereditarycharacteristics, general health, gender, diet, mode and time ofadministration, rate of excretion, drug combination, and the nature andseverity of the particular condition being treated.

Administration methods include administering an effective amount of acompound or composition of the invention at different times during thecourse of therapy or concurrently in a combination form. The methods ofthe invention include all known therapeutic treatment regimens.

Diseases and conditions associated with inflammation, immune disorders,infection and cancer may be treated or prevented with the presentcompounds, compositions, and methods. In one group of embodiments,diseases or conditions, including chronic diseases, of humans or otherspecies can be treated with an inhibitor of CCR9 function. Thesediseases or conditions include: (1) allergic diseases such as systemicanaphylaxis or hypersensitivity responses, drug allergies, insect stingallergies and food allergies, (2) inflammatory bowel diseases, such asCrohn's disease, ulcerative colitis, ileitis and enteritis, (3)vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis,eczema, atopic dermatitis, allergic contact dermatitis, urticaria andpruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma,(8) asthma and respiratory allergic diseases such as allergic asthma,allergic rhinitis, hypersensitivity lung diseases and the like, (9)autoimmune diseases, such as fibromyalagia, scleroderma, ankylosingspondylitis, juvenile RA, Still's disease, polyarticular juvenile RA,pauciarticular juvenile RA, polymyalgia rheumatica, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, polyarticular arthritis,multiple sclerosis, systemic lupus erythematosus, type I diabetes, typeII diabetes, glomerulonephritis, and the like, (10) graft rejection(including allograft rejection), (11) graft-v-host disease (includingboth acute and chronic), (12) other diseases in which undesiredinflammatory responses are to be inhibited, such as atherosclerosis,myositis, neurodegenerative diseases (e.g., Alzheimer's disease),encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis,allergic conjunctivitis, otitis, chronic obstructive pulmonary disease,sinusitis, Behcet's syndrome and gout, (13) pulmonary fibrosis and otherfibrotic diseases, and (14) irritable bowel syndrome.

Preferably, the present methods are directed to the treatment ofdiseases or conditions selected from inflammatory bowel disease,including Crohn's disease and ulcerative colitis; allergic diseases suchas psoriasis, atopic dermatitis, and asthma; and autoimmune diseasessuch as rheumatoid arthritis.

More preferably, the present methods are directed to the treatment ofinflammatory bowel disease, including Crohn's disease and ulcerativecolitis.

The compounds and compositions of the present invention can be combinedwith other compounds and compositions having related utilities toprevent and treat the condition or disease of interest, such asinflammatory conditions and diseases, including inflammatory boweldisease, allergic diseases, psoriasis, atopic dermatitis and asthma, andthose pathologies noted above. Selection of the appropriate agents foruse in combination therapies can be made one of ordinary skill in theart. The combination of therapeutic agents may act synergistically toeffect the treatment or prevention of the various disorders. Using thisapproach, one may be able to achieve therapeutic efficacy with lowerdosages of each agent, thus reducing the potential for adverse sideeffects.

The weight ratio of a compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of a compound of the present invention tothe NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Combination therapy includes co-administration of a compound of theinvention and said other agent, sequential administration of a compoundof the invention and the other agent, administration of a compositioncontaining a compound of the invention and the other agent, orsimultaneous administration of separate compositions containing acompound of the invention and the other agent.

The invention further includes the use of a compound of the invention asan active therapeutic substance, in particular in the treatment ofCCR9-mediated disorders. In particular, the invention includes the useof a compound of the invention in the treatment of inflammatory boweldisease, including Crohn's disease and ulcerative colitis.

In another aspect, the invention includes the use of compounds of theinvention in the manufacture of a medicament for use in the treatment ofthe above disorders.

“Pharmaceutically acceptable carrier” means any one or more compoundsand/or compositions that are of sufficient purity and quality for use inthe formulation of a compound of the invention that, when appropriatelyadministered to a human, do not produce an adverse reaction, and thatare used as a vehicle for a drug substance (i.e. a compound of thepresent invention).

The invention further includes the process for making the compositioncomprising mixing a compound of the invention and an optionalpharmaceutically acceptable carrier; and includes those compositionsresulting from such a process, which process includes conventionalpharmaceutical techniques. For example, a compound of the invention maybe nanomilled prior to formulation. A compound of the invention may alsobe prepared by grinding, micronizing or other particle size reductionmethods known in the art. Such methods include, but are not limited to,those described in U.S. Pat. Nos. 4,826,689, 5,145,684, 5,298,262,5,302,401, 5,336,507, 5,340,564, 5,346,702, 5,352,459, 5,354,560,5,384,124, 5,429,824, 5,503,723, 5,510,118, 5,518,187, 5,518,738,5,534,270, 5,536,508, 5,552,160, 5,560,931, 5,560,932, 5,565,188,5,569,448, 5,571,536, 5,573,783, 5,580,579, 5,585,108, 5,587,143,5,591,456, 5,622,938, 5,662,883, 5,665,331, 5,718,919, 5,747,001, PCTapplications WO 93/25190, WO 96/24336, and WO 98/35666, each of which isincorporated herein by reference. The pharmaceutical compositions of theinvention may be prepared using techniques and methods known to thoseskilled in the art. Some of the methods commonly used in the art aredescribed in Remington's Pharmaceutical Sciences (Mack PublishingCompany), the entire teachings of which are incorporated herein byreference.

The compositions of the invention include ocular, oral, nasal,transdermal, topical with or without occlusion, intravenous (both bolusand infusion), and injection (intraperitoneally, subcutaneously,intramuscularly, intratumorally, or parenterally). The composition maybe in a dosage unit such as a tablet, pill, capsule, powder, granule,liposome, ion exchange resin, sterile ocular solution, or oculardelivery device (such as a contact lens and the like facilitatingimmediate release, timed release, or sustained release), parenteralsolution or suspension, metered aerosol or liquid spray, drop, ampoule,auto-injector device, or suppository; for administration ocularly,orally, intranasally, sublingually, parenterally, or rectally, or byinhalation or insufflation.

Compositions of the invention suitable for oral administration includesolid forms such as pills, tablets, caplets, capsules (each includingimmediate release, timed release, and sustained release formulations),granules and powders.

The oral composition is preferably formulated as a homogeneouscomposition, wherein the drug substance (i.e. a compound of the presentinvention) is dispersed evenly throughout the mixture, which may bereadily subdivided into dosage units containing equal amounts of acompound of the invention. Preferably, the compositions are prepared bymixing a compound of the invention with one or more optionally presentpharmaceutical carriers (such as a starch, sugar, diluent, granulatingagent, lubricant, glidant, binding agent, and disintegrating agent), oneor more optionally present inert pharmaceutical excipients (such aswater, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and syrup), one or more optionally present conventionaltableting ingredients (such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate, and any ofa variety of gums), and an optional diluent (such as water).

Binding agents include starch, gelatin, natural sugars (e.g. glucose andbeta-lactose), corn sweeteners and natural and synthetic gums (e.g.acacia and tragacanth). Disintegrating agents include starch, methylcellulose, agar, and bentonite.

A compound of the invention may also be administered via a delayedrelease composition, wherein the composition includes a compound of theinvention and a biodegradable slow release carrier (e.g. a polymericcarrier) or a pharmaceutically acceptable non-biodegradable slow releasecarrier (e.g. an ion exchange carrier).

Biodegradable and non-biodegradable delayed release carriers are wellknown in the art. Biodegradable carriers are used to form particles ormatrices which retain a drug substance(s) (i.e. a compound of thepresent invention) and which slowly degrade/dissolve in a suitableenvironment (e.g. aqueous, acidic, basic and the like) to release thedrug substance(s). Such particles degrade/dissolve in body fluids torelease the drug substance(s) (i.e. compounds of the present invention)therein. The particles are preferably nanoparticles (e.g. in the rangeof about 1 to 500 nm in diameter, preferably about 50-200 nm indiameter, and most preferably about 100 nm in diameter). In a processfor preparing a slow release composition, a slow release carrier and acompound of the invention are first dissolved or dispersed in an organicsolvent. The resulting mixture is added into an aqueous solutioncontaining an optional surface-active agent(s) to produce an emulsion.The organic solvent is then evaporated from the emulsion to provide acolloidal suspension of particles containing the slow release carrierand a compound of the invention.

Tablets and capsules represent an advantageous oral dosage unit form.Tablets may be sugarcoated or filmcoated using standard techniques.Tablets may also be coated or otherwise compounded to provide aprolonged, control-release therapeutic effect. The dosage form maycomprise an inner dosage and an outer dosage component, wherein theouter component is in the form of an envelope over the inner component.The two components may further be separated by a layer which resistsdisintegration in the stomach (such as an enteric layer) and permits theinner component to pass intact into the duodenum or a layer which delaysor sustains release. A variety of enteric and non-enteric layer orcoating materials (such as polymeric acids, shellacs, acetyl alcohol,and cellulose acetate or combinations thereof) may be used.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples are, therefore, to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way.

EXAMPLE 1 Preparation of: An anhydrous crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

A reaction vessel was charged with 300 g4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide,4,737 mL Industrial Methylated Spirits (IMS), and 302.4 mL water. 27.245g sodium hydroxide pellets were added to the slurry at 25° C. Thereaction mixture was agitated at ambient temperature for 50 minutes,followed by heating to ˜78° C. to dissolve all solids. The clearsolution was then filtered while maintaining the temperature above 55°C. throughout the filtration process. After filtration, the filteredsolution was reheated to 75° C. and then cooled to 55° C. and seededwith 3.0 g Compound B—anhydrous crystalline form (prepared by ananalogous procedure) as a slurry in 15 mL IMS at ambient temperature.The slurry was held at 55° C. overnight and then cooled to 45° C. Vacuumdistillation was employed while heating the reactor jacket to 65° C. andnot allowing the slurry temperature to exceed 55° C., leaving ˜1,500 mLof slurry in the reactor. The slurry was cooled to −10° C., held at thattemperature overnight, and then transferred to a filter dryer andsettled for 10 minutes. The jacket temperature of the filter waspre-chilled to −10° C. The mother liquors were removed to break-throughusing 0.5 to 1 bar nitrogen pressure. The crystallizer was charged witha first pre-chilled wash of 1,200 mL IMS, chilled to −10° C. The washwas transferred to the cake in the filter, agitated for 10 minutes,settled for 10 minutes, and removed under 0.5 to 1 bar nitrogenpressure. The washing of the filter cake was repeated two additionaltimes under the same conditions. The jacket temperature of the filterwas increased to 20° C. and the cake was blown-down under 0.5 to 1 barnitrogen pressure until the solvent being removed was reduced to atrickle. The wet cake was dried at 70° C. with agitation under vacuum toprovide 258.3 g of the title compound as a yellow crystalline solid.

EXAMPLE 2 Preparation of: A crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(Compound A—1,4-dioxane/water solvate)

100 mg of an anyhydrous crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamidewas weighed into a 1.8-mL vial containing a stir bar. Water (43.9 μL),1,4-dioxane (53.0 μL), and 1 M sodium hydroxide (4.3 μL) were added, thevial was tightly capped, and the solution was stirred for 5 days at 25°C. The resulting solid was isolated using a Büchner funnel, and thefilter cake was air-dried for 1 hour to provide the title compound as ayellow solid.

The X-ray powder diffraction (XRPD) pattern of this material is shown inFIG. 1 and a summary of the diffraction angles and d-spacings is givenin Table I. The XRPD analysis was conducted on a PANanalytical X′PertPro Diffractometer, model PW3040/60, serial number DY2407 using anX′Celerator detector. The acquisition conditions included: Cu K_(α)radiation (λ=1.54059 Å), generator tension: 45 kV, generator current: 40mA, start angle: 2.0°2θ, end angle: 50.0°2θ, step size: 0.0167°2θ, timeper step: 40.005 seconds. The sample was prepared using zero background(front fill) technique.

TABLE I d-spacing Diff. Angle [°2θ] [Å] 4.0111 22.01079 8.0656 10.9530510.0893 8.76019 14.1627 6.24847 16.197 5.46795 18.6342 4.75791 20.31184.36857 24.6832 3.60392 24.9557 3.56518 26.5095 3.35963

The Raman spectrum of the title compound was recorded on a Nicolet NXR9650 FT-Raman Spectrometer, at 4 cm⁻¹ resolution with excitation from aNd:YVO4 laser (λ=1064 nm). The Raman spectrum of this material is shownin FIG. 6 with major peaks observed at 668, 743, 804, 1125, 1154, 1162,1286, 1544, 1587, 1597, 1611, 1657, and 1672 cm⁻¹.

The differential scanning calorimetry (DSC) thermogram of the titlecompound was recorded on a TA Instruments Q1000 Differential Scanningcalorimeter and is shown in FIG. 10. The sample was weighed into analuminium pan, a pan lid placed on top and lightly crimped withoutsealing the pan. The experiments were conducted using a heating rate of15° C./min.

The thermogravimetric analysis (TGA) thermogram of the title compoundwas recorded on a TA Instruments Q5000 Themrogravimetric Analyzer and isshown in FIG. 14. The experiments were conducted using a heating rate of15° C./min.

EXAMPLE 3 Preparation of: A crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(Compound A—formamide solvate)

300 mg of an anyhydrous crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamidewas weighed into a 4-mL vial containing a stir bar. Dichloromethane(1,050 μL), formamide (450 μL), and 0.5 M sodium methoxide (38.4 μL)were added sequentially. The suspension was heated to 40° C. and stirredfor 30 minutes. The sample was cooled to 0° C. at 1° C./minute and thenstirred for an additional 30 minutes. The resulting solid was isolatedusing a Büchner funnel, and the filter cake was washed with colddichloromethane (4 mL, pre-cooled to 1° C.), and dried at 50° C. for 30minutes to provide the title compound as a yellow solid.

The X-ray powder diffraction (XRPD) pattern of this material is shown inFIG. 2 and a summary of the diffraction angles and d-spacings is givenin Table II. The XRPD analysis was conducted on a PANanalytical X′PertPro Diffractometer, model PW3040/60, serial number DY2407 using anX′Celerator detector. The acquisition conditions included: Cu K_(α)radiation (λ=1.54059 Å), generator tension: 45 kV, generator current: 40mA, start angle: 2.0°2θ, end angle: 50.0°2θ, step size: 0.0167°2θ, timeper step: 40.005 seconds. The sample was prepared using zero background(front fill) technique.

TABLE II d-spacing Diff. Angle [°2θ] [Å] 5.878 15.02355 8.6404 10.2256612.0513 7.33805 12.6593 6.98695 16.125 5.4922 16.9097 5.23907 17.41145.08922 17.7555 4.99136 18.0075 4.92206 20.3906 4.35187 20.6226 4.3034321.7359 4.08548 22.5655 3.93711 23.749 3.74352 23.8983 3.72046 24.29963.65992 25.8941 3.43805 26.2873 3.38752 26.5418 3.35561 26.8984 3.3119327.9099 3.19415 30.8679 2.89447 38.6418 2.32818

The Raman spectrum of the title compound was recorded on a Nicolet NXR9650 FT-Raman Spectrometer, at 4 cm⁻¹ resolution with excitation from aNd:YVO4 laser (λ=1064 nm). The Raman spectrum of this material is shownin FIG. 7 with major peaks observed at 655, 668, 737, 804, 1079, 1099,1123, 1161, 1229, 1303, 1465, 1537, 1595, 1611, and 1654 cm⁻¹.

The differential scanning calorimetry (DSC) thermogram of the titlecompound was recorded on a TA Instruments Q1000 Differential Scanningcalorimeter and is shown in FIG. 11. The sample was weighed into analuminium pan, a pan lid placed on top and lightly crimped withoutsealing the pan. The experiments were conducted using a heating rate of15° C./min.

The thermogravimetric analysis (TGA) thermogram of the title compoundwas recorded on a TA Instruments Q5000 Themrogravimetric Analyzer and isshown in FIG. 15. The experiments were conducted using a heating rate of15° C./min.

EXAMPLE 4 Preparation of: A crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(Compound A—dimethylsulfoxide solvate)

100 mg of an anyhydrous crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamidewas weighed into a 2-mL vial containing a stir bar. Chlorobenzene (350μL), dimethylsulfoxide (150 μL), and 0.5 M sodium methoxide (12.5 μL)were added sequentially. The suspension was stirred at 25° C. for 3weeks. The resulting solid was isolated on filter paper, and the filtercake was dried at 40° C. for 2 hours to provide the title compound.

The X-ray powder diffraction (XRPD) pattern of this material is shown inFIG. 3 and a summary of the diffraction angles and d-spacings is givenin Table III. The XRPD analysis was conducted on a PANanalytical X′PertPro Diffractometer, model PW3040/60, serial number DY2407 using anX′Celerator detector. The acquisition conditions included: Cu K_(α)radiation (λ=1.54059 Å), generator tension: 45 kV, generator current: 40mA, start angle: 2.0°2θ, end angle: 50.0°2θ, step size: 0.0167°2θ, timeper step: 40.005 seconds. The sample was prepared using zero background(front fill) technique.

TABLE III d-spacing Diff. Angle [°2θ] [Å] 5.5934 15.7874 7.9864 11.0614310.7791 8.20108 15.6579 5.65498 16.9909 5.2142 17.7411 4.99539 17.98334.92863 18.1354 4.88764 18.4398 4.80765 21.2071 4.18612 21.7596 4.0810722.5174 3.94542 22.7501 3.90558 24.2764 3.66338 28.5661 3.12225 29.6943.00618 34.461 2.60046

The Raman spectrum of the title compound was recorded on a Nicolet NXR9650 FT-Raman Spectrometer, at 4 cm⁻¹ resolution with excitation from aNd:YVO4 laser (λ=1064 nm). The Raman spectrum of this material is shownin FIG. 8 with major peaks observed at 662, 672, 718, 729, 750, 799,1078, 1109, 1158, 1236, 1302, 1536, 1588, 1596, and 1636 cm⁻¹.

The differential scanning calorimetry (DSC) thermogram of the titlecompound was recorded on a TA Instruments Q1000 Differential Scanningcalorimeter and is shown in FIG. 12. The sample was weighed into analuminium pan, a pan lid placed on top and lightly crimped withoutsealing the pan. The experiments were conducted using a heating rate of15° C./min.

The thermogravimetric analysis (TGA) thermogram of the title compoundwas recorded on a TA Instruments Q5000 Themrogravimetric Analyzer and isshown in FIG. 16. The experiments were conducted using a heating rate of15° C./min.

EXAMPLE 5 Preparation of: A crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(Compound A—desolvated crystalline form)

100 mg of a crystalline formamide solvate of a sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(Compound A—formamide solvate) was placed onto an aluminum TGA pan andheated to 260° C. at a rate of 15° C./minute using a TA InstrumentsQ5000 Themrogravimetric Analyzer to provide the title compound.

The X-ray powder diffraction (XRPD) pattern of this material is shown inFIG. 4 and a summary of the diffraction angles and d-spacings is givenin Table IV. The XRPD analysis was conducted on a PANanalytical X′PertPro Diffractometer, model PW3040/60, serial number DY2407 using anX′Celerator detector. The acquisition conditions included: Cu K_(α)radiation (λ=1.54059 Å), generator tension: 45 kV, generator current: 40mA, start angle: 2.0°2θ, end angle: 50.0°2θ, step size: 0.0167°2θ, timeper step: 40.005 seconds. The sample was prepared using zero background(front fill) technique.

TABLE IV d-spacing Diff. Angle [°2θ] [Å] 6.4791 13.63095 9.586 9.2189410.6185 8.32478 11.9048 7.42802 14.4414 6.12848 16.0781 5.50811 17.69855.0073 17.9351 4.94178 19.3172 4.59121 21.0851 4.21008 21.9857 4.0396122.2374 3.99444 23.3765 3.80232 23.6316 3.76185 24.432 3.64039 26.26673.39013 27.7153 3.21614 28.5025 3.12908 29.5187 3.02363

The Raman spectrum of the title compound was recorded on a Nicolet NXR9650 FT-Raman Spectrometer, at 4 cm⁻¹ resolution with excitation from aNd:YVO4 laser (λ=1064 nm). The Raman spectrum of this material is shownin FIG. 9 with major peaks observed at 654, 667, 737, 803, 855, 1077,1122, 1160, 1311, 1461, 1536, 1592, 1609, and 1648 cm⁻¹.

The differential scanning calorimetry (DSC) thermogram of the titlecompound was recorded on a TA Instruments Q1000 Differential Scanningcalorimeter and is shown in FIG. 13. The sample was weighed into analuminium pan, a pan lid placed on top and lightly crimped withoutsealing the pan. The experiments were conducted using a heating rate of15° C./min.

The thermogravimetric analysis (TGA) thermogram of the title compoundwas recorded on a TA Instruments Q5000 Themrogravimetric Analyzer and isshown in FIG. 17. The experiments were conducted using a heating rate of15° C./min.

EXAMPLE 6 Preparation of: A crystalline sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(Compound A—hydrate)

Approximately 30 mg of a desolvated crystalline form of a sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(Compound A—desolvated crystalline form) placed on a flat XRPD sampleholder and left standing in a fume hood for 5 weeks to provide the titlecompound mixed with some of the starting desolvated material.

The X-ray powder diffraction (XRPD) pattern of this material is shown inFIG. 5 and a summary of the diffraction angles and d-spacings is givenin Table V. The XRPD analysis was conducted on a PANanalytical X′PertPro Diffractometer, model PW3040/60, serial number DY2407 using anX′Celerator detector. The acquisition conditions included: Cu K_(α)radiation (λ=1.54059 Å), generator tension: 45 kV, generator current: 40mA, start angle: 2.0°2θ, end angle: 50.0°2θ, step size: 0.0167°2θ, timeper step: 40.005 seconds. The sample was prepared using zero background(front fill) technique.

TABLE V d-spacing Diff. Angle [°2θ] [Å] 6.1432 14.37558 12.3809 7.1433715.9257 5.56049 16.4099 5.39747 16.8501 5.25745 17.7646 4.98883 18.03884.9136 19.126 4.63667 23.443 3.79169 25.0165 3.55664

The thermogravimetric analysis (TGA) thermogram of the product wasrecorded on a TA Instruments Q5000 Themrogravimetric Analyzer and isshown in FIG. 18. The experiments were conducted using a heating rate of15° C./min.

1-18. (canceled)
 19. A crystalline form of a sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide,wherein the crystalline form is characterized by an X-ray powderdiffraction pattern containing diffraction angles, when measured usingCu K_(α) radiation, at about 6.5, 9.6, 10.6, 11.9, 14.4, 16.1, 17.7,17.9, 19.3, 21.1, 22.0, 22.2, 23.4, 23.6, 24.4, 26.3, 27.7, 28.5, and29.5°2θ.
 20. A crystalline form of a sodium salt of4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide,wherein the crystalline form is characterized by an X-ray powderdiffraction pattern substantially in accordance with FIG.
 4. 21. Thecrystalline form of claim 20, wherein the crystalline form provides aRaman spectrum containing peaks at about 654, 667, 737, 803, 855, 1077,1122, 1160, 1311, 1461, 1536, 1592, 1609, and 1648 cm⁻¹.
 22. Thecrystalline form of claim 20, wherein the crystalline form provides aRaman spectrum substantially in accordance with FIG.
 9. 23. Apharmaceutical composition comprising the crystalline form according toclaim 20 and a pharmaceutically acceptable carrier.
 24. A method ofpreparing a pharmaceutical composition comprising admixing thecrystalline form according to claim 20 and a pharmaceutically acceptablecarrier. 25-28. (canceled)
 29. The crystalline form of claim 20, whereinthe crystalline form differential scanning calorimetry thermogramprofile is substantially in accordance with FIG.
 13. 30. The crystallineform of claim 20, wherein the crystalline form thermogravimetricanalysis thermogram profile is substantially in accordance with FIG. 17.31. A method of treating a CCR9-mediated disorder, comprisingadministering an effective amount of the pharmaceutical composition ofclaim 23 to a patient in need thereof.
 32. A method of treating aCCR9-mediated disorder in a subject in need thereof comprisingadministering to the subject an effective amount of the crystalline formof claim
 20. 33. The method of claim 32 wherein the CCR9-mediateddisorder is an inflammatory bowel disease.
 34. The method of claim 33wherein the inflammatory bowel disease is selected from Crohn's diseaseand ulcerative colitis.
 35. The method of claim 32, wherein theCCR9-mediated disorder is selected from allergic diseases, vaginitis,psoriasis, inflammatory dermatoses, vasculitis, spondyloarthropathies,scleroderma, asthma, respiratory allergic diseases, autoimmune diseases,graft rejection, graft-v-host disease, other diseases with inflammatoryresponses, fibrotic diseases, and irritable bowel syndrome.
 36. Themethod of claim 35, wherein the allergic disease is selected fromsystemic anaphylaxis or hypersensitivity responses, drug allergies,insect sting allergies, and food allergies.
 37. The method of claim 35,wherein the inflammatory dermatoses is selected from dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria and pruritus.38. The method of claim 35, wherein the respiratory allergic disease isselected from allergic asthma, allergic rhinitis, hypersensitivity lungdisease.
 39. The method of claim 35, wherein the autoimmune disease isselected from fibromyalagia, scleroderma, ankylosing spondylitis,juvenile RA, Still's disease, polyarticular juvenile RA, pauciarticularjuvenile RA, polymyalgia rheumatica, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, polyarticular arthritis, multiple sclerosis,systemic lupus erythematosus, type I diabetes, type II diabetes, andglomerulonephritis.
 40. The method of claim 35, wherein the otherdiseases with inflammatory responses are selected from atherosclerosis,myositis, neurodegenerative diseases, encephalitis, meningitis,hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis,otitis, chronic obstructive pulmonary disease, sinusitis, Behcet'ssyndrome, and gout.
 41. The method of claim 40, wherein theneurodegenerative disease is Alzheimer's disease.
 42. The method ofclaim 35, wherein the fibrotic disease is pulmonary fibrosis.